Sphingosine 1-phosphate (S1P) is a small signaling lipid molecule that is present in low concentrations in the plasma membrane of nearly all eukaryotic cells and at high concentrations in serum. S1P is generated by the phosphorylation of sphingosine by sphingosine kinase (SphK) and acts on a family of five known S1P-selective G protein-coupled receptors (the five subtypes designated as S1P1, S1P2, S1P3, S1P4, and S1P5). These receptors couple to a number of G-proteins and down-stream effectors to elicit a variety of cellular responses. The responses vary depending on the expression profile of the receptors and effectors, but notably include proliferation, survival, and cytoskeletal rearrangement.
S1P and its receptors have been implicated as playing a role in cancer. Not all receptor subtypes appear to play an equal role in cancer and blocking some subtypes could elicit harmful side effects and might even promote cancer. For example, FTY720 is a broad-spectrum S1P receptor inverse agonist that has been reported to effectively inhibit four of the five known receptors (with the exception of S1P2) by stable internalization. Administration of FTY720 has been shown to inhibit angiogenesis and subsequent growth in a tumor transplant model. This effect is mediated through the functional antagonism of S1P1 and S1P3. S1P3 is also known as EDG3, EDG-3, S1PR3, and LPB3. An unfortunate side-effect of S1P1 antagonism is marked lymphopenia and immunosuppression. Accordingly, there is a significant need in the art for S1P3 selective antagonists that would retain the tumor-suppressive and anti-angiogenic properties of FTY720 without the immunosuppression associated with S1P1 antagonism.
Although there are many chemotherapeutic medications on the market, few, if any, of these medications appear to be sufficient to consistently treat cancer in patients. Accordingly, it is a further object of this invention to identify anti-neoplastic agents that can enhance the efficacy of existing chemotherapeutics.
Coagulation is one of the principal features of systemic inflammatory response syndromes in bacterial sepsis and viral hemorrhagic fevers. While some anticoagulants can show efficacy in severe sepsis with disseminated intravascular coagulation, there remains a considerable need for new therapeutics in these areas. New methods of and agents for preventing disseminated intravascular coagulation are sought.